One of the emerging themes in cancer biology is the dependence of cancer subtypes on certain signaling pathways for continued tumor growth. For example, mutations that activate the Hedgehog (Hh) signaling pathway drive growth of a variety of cancers including basal cell carcinomas (BCCs) and medulloblastomas, along with pancreatic, prostate, and small cell lung cancer that account for up to 25% of all human cancer deaths (Epstein, Nat. Rev. Cancer 8:743-754 (2008)). BCCs are the most prevalent cancer in the world, and nearly half of all US citizens are likely to develop this cancer before retirement (NCI 2010). Twenty years of extensive research identifying Hh pathway components and their functional roles recently culminated in the FDA approved Hh pathway antagonist vismodegib for the treatment of locally advanced or metastatic BCCs. Although vismodegib effective, not all tumor cells are sensitive to the drug and further resistance can develop.
Human LGR5 is a 907 amino acid protein, of which ˜540 amino acids are predicted to be in the extracellular space following cleavage of the amino-terminal signal sequence. LGR5 comprises 17 imperfect leucine-rich repeat motifs in the ectodomain, and a cysteine-rich region located between the leucine-rich repeats and the first transmembrane domain.